This invention relates to novel quinazoline derivatives, for example 4-(3xe2x80x2-bromobenzoyl)-6,7-dimethoxyquinazoline), and methods of use. In particular, the compounds of the invention, when administered to a subject, are effective in reducing blood cholesterol levels in the subject.
Atherosclerosis and ischemic heart disease remain the major cause of death of Americans. Elevated serum cholesterol levels present a major risk factor for atherosclerosis and related complications including myocardial infarction, heart failure, and cerebral stroke. Intervention studies performed in middle-aged men demonstrated a marked reduction in the incidence of cardiovascular events after the lowering of elevated total and low-density lipoprotein cholesterol (LDL-C) levels. The Cholesterol and Recurrent Events (CARE) trial and the Scandinavian Simvastatin Survival Study (4S)(1994, Lancet 344:1383-1389) have further shown that both women and elderly patients with prior history of ischemic heart disease benefit from cholesterol lowering therapy. (Miettinen et al., 1988, Arch. Intern. Med. 148:36-69; Sacks et al., 1996, New Eng. J Med. 335:1001-1009)
The most effective cholesterol lowering drugs are statins, which lower cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme which catalyzes the limiting step in cholesterol biosynthesis (Goldstein et.al., 1984, J. Lipid Res. 25, 1450-1461). Compared to treatment regimens with other lipid lowering agents, such as the bile acid sequestrants (colestipol and cholestyramine), nicotinic acid, fibric acid (gemfibrozil and clofibrate), probucol, and experimental ACAT inhibitors, statin therapy has been found to bear several favorable features. Statins achieve extensive lowering of LDL-C, leading to an overall reduction in mortality, and are cost effective due to substantial reduction of hospital admissions and rates of coronary intervention. Statins also achieve better compliance than other treatments, as a result of their once-daily administration and few side effects. Combination of statins with other agents is considered necessary for patients with severe, complex or refractory lipid disorders. Furthermore, large clinical trials have suggested regression of atherosclerotic lesions by aggressive lipid lowering therapy (Schell and Myers, 1997, Prog. on Cardiovascular Diseases 39:483-496). To complement the statins and achieve successful reduction of cholesterol in statin-resistant subjects, identification of new lipid lowering agents with a different mechanism of action than statins remains a major focal point in contemporary atherosclerosis research. Since the HMG CoA inhibitors are ineffective in the mouse, this animal provides a useful model for screening novel agents capable of lowering cholesterol levels by a different mechanism of action than statins.
There is a need for new lipid lowering agents that are effective to lower total cholesterol and/or LDL-C, for the treatment of high cholesterol and other lipid disorders including those which are severe, complex, and/or refractory to current treatments.
Quinazoline compounds having a carbonyl substitution (carbonyl-Q) as described below and exemplified by 4-(3xe2x80x2-bromobenzoyl)-6,7-dimethoxyquinazoline (WHI-P164) have now been identified as a new class of potent cholesterol lowering agents. As shown in the Examples below, administration of the WHI-P164 reduces total cholesterol levels in hypercholesterolemic C57B1/6 mice on a high calorie diet by 23% and LDL-C by 45%. WHI-P164 also reduced total cholesterol levels and xcex2-VLDL/LDL-cholesterol levels of hypercholesterolemic apolipoprotein E deficient mice (apo exe2x88x92/xe2x88x92) by 41% and 63%, respectively.
The present invention provides potent cholesterol-lowering agents, quinazoline compounds having a carbonyl group, (carbonyl-Q). An exemplary compound of the invention is 4-(3 xe2x80x2-bromobenzoyl)-6,7-dimethoxyquinazoline).
The novel cholesterol lowering agents of the invention may be formulated by means known in the art for delivery to targeted areas of the body, including blood and/or gut, for example, by choice of carrier, mode of administration, or by conjugating carbonyl-Q with a specific targeting moiety, such as an antibody or ligand which binds a specific antigen or ligand receptor in the target tissue. Formulations useful for therapeutic reduction of cholesterol include injectable compositions, oral compositions, depot formulations, and the like containing an effective cholesterol-lowering amount of a carbonyl-Q compound of the invention, such as 4-(3xe2x80x2-bromobenzoyl)-6,7-dimethoxyquinazoline.
In the methods of the invention, carbonyl-Q cholesterol lowering agents such as 4-(3xe2x80x2-bromobenzoyl)-6,7-dimethoxyquinazoline are administered to a subject in order to modulate lipids in the blood, and particularly to lower blood cholesterol.
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The examples and the detailed description which follow more particularly exemplify these embodiments.